PROJECT SUMMARY This five-year K08 proposal will provide the candidate, Juyong Brian Kim, with rigorous training to fulfill specific needs in research and professional development and successfully launch his independent physician-scientist career. The long-term goals are to prepare the candidate for a life-long career as a physician-scientist focused on atherosclerosis and to ultimately improve the management of patients with atherosclerosis through the development of novel therapeutics. The candidate's primary mentor is Dr. Thomas Quertermous, who is an internationally renowned expert in high-throughput genetics, transcriptional regulatory mechanisms, and vascular biology. The candidate is also supported by a committee of advisors and collaborators with expertise in vascular biology and disease, epigenetics and genomics (Drs. William Greenleaf, Gary Owens, Marlene Rabinovitch, Phil Tsao, and Sean Wu). Collectively, the candidate, mentor and advisory committee have formulated a career development plan that will: i) develop the candidate's scientific background for successful research in an important area that parallels his clinical interests; ii) facilitate the candidate's acquisition of new technical skills in cellular and molecular biology and genetics; and iii) provide a mentored transition period between postdoctoral training and independent investigation. The training plan consists of dedicated research time, attendance at meetings to present original work, leadership development, attendance of academic seminars, lectures and journal clubs, formal and informal meetings with the mentor and advisory committee, as well as formal training in the responsible conduct of research. All key personnel have vast experience in the mentorship of trainees. Additionally, Stanford University is committed to providing a maximally supportive environment for the candidate's career development. The candidate will have all resources, infrastructure and support in place to ensure success. The candidate has newly renovated and well equipped laboratory space, the support of clinical colleagues and support staff to ensure at least 80% of his time is protected for research and the support of an abundance of core facilities and shared resources offered through the School of Medicine and through the laboratories of the mentor and advisory committee. Stanford University provides the ideal environment for the candidate's career development. The research topic of this proposal fulfills a significant knowledge gap in the field by identifying a novel mechanism leading to smooth muscle cell inflammation and plaque instability in atherosclerotic lesions. Atherosclerosis is a genetically complex trait that claims more lives than cancer, lung disease and accidents combined. The candidate proposes several hypothesis-driven approaches that will address critical gaps in understanding the genetic basis of atherosclerosis. In Specific Aim 1, the candidate will define the function of TCF21 gene on the inflammatory phenotype of coronary artery smooth muscle cells based on preliminary findings that TCF21 modulates pro-inflammatory networks. He also proposes to untangle the nature of the interaction between TCF21 and environmental toxins and oxidized lipids, as it relates to gene by environment interaction contributing to atherosclerosis. In Specific Aim 2, the candidate will define the function of TCF21 on smooth muscle cell inflammation and lesion stability using mouse models of atherosclerosis. Ultimately, this work will shed light on novel pathways and networks associated with risk for atherosclerosis, leading to development of new class of therapeutics. Thus, the proposed work is of high translational potential. The aims of this project are aligned with the major strategic goal of NHLBI to improve our understanding of the molecular and physiologic basis of health and disease.